Intrauterine growth restriction (IUGR) in developed countries accounts for 4-8% of all births and increases perinatal morbidity and mortality. The leading cause of IUGR is decreased nutrient supply to the developing fetus, which results in asymmetric fetal growth due to fetal compensatory mechanisms that maintain viability by sparing critical organs at the expense of others. Epidemiological evidence indicates that IUGR small for gestational age (SGA) infants have a higher susceptibility for adult diseases including non-insulin dependent diabetes mellitus (NIDDM). An explanation for this increased predisposition to NIDDM in adulthood may be fetal programming of structure, physiology, and/or metabolism of pancreatic endocrine cells. Pancreatic beta-cells/islets secrete catabolic and anabolic hormones, which play a central role in regulating metabolism. Therefore, if beta-cell growth and differentiation are reduced by nutrient deprivation, lasting consequences may include decreased beta-cell responsiveness (i.e. decreased insulin secretion capacity) and NIDDM. Additionally, reductions of beta-cell function can be produced by regulatory genes that are structurally changed or epigenetically altered to create a different and lasting functional program. The long-term goal of this project is to determine mechanisms of fetal programming. Specifically, this proposal will examine endocrine pancreas morphometry and development in placental insufficiency IUGR sheep fetuses to characterize this model for fetal pancreatic programming. First we will determine pancreatic developmental stages in the normal fetus during gestation, and subsequently determine deficiencies in beta-cell differentiation and growth that occur in nutrient deprived IUGR fetuses. Additionally, pancreas morphology will be examined for aberrant mesenchymal-epithelial interaction to begin to identify the role of paracrine factors on pancreas endocrine development. Next we will examine gene expression profiles using microarrays to identify regulatory genes that limit pancreas development and/or function by fetal placental insufficiency. We postulate that reductions in fetal beta-cell mass are resulting from decreased beta-cell neogenesis due to limitation in endocrine precursor cells. Gene expression profiles for the developing and IUGR pancreases will be examined to identify regulatory genes involved in programming pancreatic architecture and/or beta-cell function, which lead to reduced insulin secretion responsiveness. These studies will identify mechanisms of fetal programming, be they genetic, structural, or a combination of both, that alter an individual's life-long physiology, providing a firmer foundation for the scientific basis of "fetal origins of adult disease."